The Grignard reaction is one of the most commonly used methods of carbon-carbon bond formation (Grignard (1900), Richey (1999)). It is an organometallic chemical reaction in which alkyl, vinyl, or aryl magnesium halides, termed “Grignard reagents”, add to an electrophilic carbon to form a carbon-carbon bond. The Grignard reagent functions as a nucleophile, attacking an electrophilic carbon atom present in a reactant molecule such a carbonyl group of a ketone or an aldehyde or a C═N group of an imine.
The addition of the Grignard reagent to an electrophilic carbon atom typically proceeds through a six-membered ring transition state, and this is shown for a ketone in the scheme below:

The Grignard reaction is, however, typically non-stereoselective forming racemic products such as racemic alcohols and amines.
Chiral alcohols and chiral amines are, however, essential structural motifs for a number of pharmaceutical and natural products. Thus the development of an asymmetric Grignard synthesis for these compounds is of fundamental interest.
Unfortunately, however, asymmetric C—C bond formation by the Grignard reaction is still amongst the most poorly developed fields of organic synthesis (Walsh et al. (2009); Noyori et al. (1991); Luderer et al. (2009); Corey et al. (1998)), and there are only a few examples of asymmetric 1,2-addition of a Grignard reagent to ketones (Manabu et al. (2008)).
The challenges in the development of an asymmetric Grignard reaction include:
(i) competition from background non-stereoselective reactions,
(ii) reduced enantioface discrimination when there are similar groups either side of the electrophilic carbon, and
(iii) reduced yields due to competing enolisation and reduction side reactions.
A number of strategies have been employed in the synthesis of chiral alcohols and chiral amines.
In principle, the most direct route is to resolve the racemic alcohol or amine. Resolution can be achieved using for example biological, usually enzymatic, methods. Resolution is, however, inefficient as it requires extra manufacturing steps to dispose or recycle the unwanted stereoisomer, and biological methods may also often be specific to one particular compound.
Asymmetric Grignard synthesis of alcohols and amines has previously involved transmetallation to copper, zinc, titanium or aluminium (Shibasaki et al. (2008); Fandrick et al. (2011); Tomita et al. (2005); Ashoka et al. (2012); Pu et al. (2001); DiMauro et al. (2002); Dosa et al. (1998); (Ramón (1998); Friel et al. (2008)). These methods were, however, found to have significant defects including a limited scope of reaction, an undesirable inorganic waste generation and a large excess of metal source.
Other approaches to asymmetric Grignard synthesis have used organolithium species (Noyori et al. (1988)), or organocopper species and a chiral phosphine ligand (Madduri et al. (2012)). Again, however, these approaches were found to have defects such as a limited scope of reaction and produce a low enantiomeric excess of chiral product.
Weber et al. (1992) reported a successful asymmetric 1,2-addition of Grignard reagents to ketones. However, the chiral ligand used in this process was TADDOL (α, α, α′, α′-tetraaryl-1,3-dioxolan-4,5-dimethanol), which remained difficult to separate from the products and gave rise to moderate yields.
US 2004/0249184 discloses chiral phosphane ligands which are useful for the production of catalysts for asymmetric hydrosilylation, amination, alkyl substitution and Grignard coupling.
WO 99/50205 discloses a process for preparing a single enantiomer of an α,α-disubstituted-α-hydroxy acetic acid, such as cyclohexylphenylglycolic acid, using cyclic 1,2-aminoalcohols and Grignard reagents. The process involves reacting a prochiral α-ketocarboxylic acid with a single enantiomer of an N-substituted vicinal aminoalcohol of cyclopentane, cyclohexane, indane, tetralin or benzosuberane to form an ester of the α-ketocarboxylic acid, reacting this ester with an excess of a Grignard reagent to form a diasteromer of the α-hydroxycarboxylate ester, separating and optionally hydrolysing the single diastereomer to provide an α-hydroxycarboxylic acid or salt enriched in one enantiomer.
CN101844958 discloses a method for synthesising a chiral secondary alcohol using an aryl Grignard reagent, aluminium halide, a passivator, a TADDOL ligand or BINOL or BINOL derivatives thereof, and titanium tetraisopropoxide.
There therefore remains a clear need for a process which stereoselectively prepares chiral compounds using the Grignard reaction. Such a process would be particularly useful for preparing chiral alcohols and chiral amines which have important uses in developing pharmaceutical and natural products.